Drug delivery devices with drug-permeable component and methods

ABSTRACT

Drug delivery devices having a drug-permeable component and methods of making and using the same are provided. Drug delivery devices include a housing having a first and second wall structures that are adjacent one another and together form a tube defining a drug reservoir lumen. The second wall structure, or both the first wall structure and the second wall structure, are permeable to water, and the first wall structure is impermeable to the drug while the second wall structure is permeable to the drug, such that the drug is releasable in vivo by diffusion through the second wall structure.

CROSS-REFERENCE TO RELATED APPLICATIONS

This application is divisional of U.S. application Ser. No. 15/137,837,filed Apr. 25, 2016, which claims priority to U.S. ProvisionalApplication No. 62/151,982, filed Apr. 23, 2015 and to U.S. ProvisionalApplication No. 62/293,232, filed Feb. 9, 2016, all of which areincorporated herein by reference.

BACKGROUND

The present disclosure is generally in the field of medical devices, andmore particularly relates to drug delivery devices for insertion intothe body of patient for controlled release of drug, including but notlimited to devices deployable in the urinary bladder for administrationof drug into the bladder.

Intravesical drug delivery devices are known. Examples of such devicesare described in U.S. Pat. No. 8,679,094 to Cima et al., U.S. Pat. No.9,017,312 to Lee et al., U.S. Pat. No. 9,107,816 to Lee et al., and U.S.Patent Application Publication No. 2012/0089121 A1 to Lee et al. In someembodiments, the intravesical devices include a water permeable housingdefining a drug reservoir lumen which contains a solid or semi-soliddrug formulation, and release of the drug in vivo occurs by water fromthe bladder diffusing into drug reservoir lumen to solubilize the drug,and then an osmotic pressure build-up in the drug reservoir lumen drivesthe solubilized drug out of the device through a release aperture.

In some cases, e.g., with certain drugs and therapeutic applications, itwould be desirable to extend the period over which a therapeutic amountof the drug is released and/or to keep the drug from coming out tooquickly. One way of accomplishing this is by retarding the rate at whichthe water can enter the drug reservoir. U.S. Patent ApplicationPublication No. 2009/0149822 A1 to Cima et al. discloses adding aconformal coating or sheath over at least a portion of an outer surfaceof the housing to reduce the water-permeability of the housing. However,this approach complicates manufacturing. Furthermore, because the devicehousing of these intravesical devices typically are designed to beelastically deformable, maintaining an effective coating may bechallenging, since the coating may delaminate and/or crack during devicedeformation, which could undesirably alter the drug release kinetics andnegatively impact reproducibility of results.

U.S. Patent Application Publication No. 2014/0276636 A1 to Lee et al.discloses devices in which drug is released from a housing made of afirst wall structure and a hydrophilic second wall structure, whereinthe first wall structure is impermeable to the drug and the second wallstructure is permeable to the drug. It would be desirable to provideimprovements and/or alternative embodiments to these devices, to providedevices capable of delivering drugs at effective release rates for arange of different drugs, and to provide methods for making thesedevices with greater flexibility of and control over the relative sizesand locations of the two wall structures.

SUMMARY

In a first aspect, a drug delivery device includes a housing having afirst wall structure and a second wall structure that are adjacent oneanother and together form a tube defining a drug reservoir lumen, and adrug contained in the drug reservoir lumen. The second wall structure,or both the first wall structure and the second wall structure, arepermeable to water, and the first wall structure is impermeable to thedrug and the second wall structure is permeable to the drug, such thatthe drug is releasable in vivo by diffusion through the second wallstructure. The second wall structure occupies less than 90 percent of across sectional area of the tube, in a cross section normal to thelongitudinal axis of the tube, and the first wall structure contains afirst polyurethane composition.

In a second aspect, a drug delivery device includes an elongated,elastic housing having a drug reservoir lumen extending between a firstclosed end and a second closed end, and a drug contained in the drugreservoir lumen. The housing includes a tubular wall structure that isformed of a first annular segment formed entirely of a first materialwhich is impermeable to the drug, and a second annular segment formed atleast partially of a second material which is permeable to the drug andconfigured to release the drug in vivo by diffusion through the secondmaterial in the second annular segment. The first annular segment has afirst end which is integrally formed and connected with a first end ofthe second annular segment.

In a third aspect, a drug delivery device includes a tubular housinghaving a closed drug reservoir lumen bounded by a wall structurecontaining at least one thermoplastic material, and a drug contained inthe drug reservoir lumen. At least a portion of the wall structure iswater permeable and at least a portion of the wall structure ispermeable to the drug such that the drug is releasable in vivo bydiffusion through the drug permeable portion of the wall structure. Thetubular housing is elastically deformable from a coiled retention shapesuited to retain the device within the urinary bladder of a patient toan uncoiled shape suited for insertion of the device through thepatient's urethra and into the bladder, and the tubular housing isthermally shape set to have the coiled retention shape.

In a fourth aspect, a method of making a drug delivery device having anelongated, elastic housing having a drug reservoir lumen extendingbetween a first end and a second end, includes (i) forming a firstannular segment entirely of a first material, which is impermeable to adrug to be delivered, by an extrusion process which includes introducingthe first material into an extrusion stream, and (ii) forming a secondannular segment at least partially of a second material, which ispermeable to the drug to be delivered, by intermittently introducing thesecond material into the extrusion stream with the first material and atpreselected positions, effective to form a tubular structure having oneor more first annular segments integrally connected to one or moresecond annular segments.

In a fifth aspect, a method of administering a drug to a patient in needthereof includes inserting into the patient a device including (i) ahousing having a first wall structure and a second wall structure thatare adjacent one another and together form a tube defining a drugreservoir lumen, and (ii) a drug contained in the drug reservoir lumen,wherein the first wall structure is impermeable to the drug and containsa polyurethane, the second wall structure is permeable to the drug andoccupies less than 90 percent of the external surface area of the tube,and wherein the second wall structure, or both the first wall structureand the second wall structure, are permeable to water. The methodfurther includes permitting water to be imbibed through only the secondwall structure or through both the first and second wall structures tosolubilize the drug, and permitting the solubilized drug to be releasedfrom the device by diffusion through the second wall structure.

In a sixth aspect, a method of administering a drug to a patient in needthereof includes inserting into the patient a device including (i) anelongated, elastic housing having a tubular wall structure and a drugreservoir lumen extending between a first closed end and a second closedend, and (ii) a drug contained in the drug reservoir lumen, wherein thewall structure includes a first annular segment formed entirely of afirst material which is impermeable to the drug and a second annularsegment formed at least partially of a second material which ispermeable to the drug, the first annular segment having a first endwhich is integrally formed and connected with a first end of the secondannular segment. The method further includes permitting water to beimbibed through the tubular wall structure to solubilize the drug, andpermitting the solubilized drug to be released from the device bydiffusion through the second annular segment of the tubular wallstructure.

BRIEF DESCRIPTION OF THE DRAWINGS

The detailed description is set forth with reference to the accompanyingdrawings. The use of the same reference numerals may indicate similar oridentical items. Various embodiments may utilize elements and/orcomponents other than those illustrated in the drawings, and someelements and/or components may not be present in various embodiments.Elements and/or components in the figures are not necessarily drawn toscale.

FIG. 1A is a longitudinal cross-sectional view of one embodiment of adrug delivery device in a coiled retention shape, in accordance with thepresent disclosure.

FIG. 1B is a traverse cross-sectional view of the drug delivery deviceof FIG. 1A, in accordance with the present disclosure.

FIG. 2 is a traverse cross-sectional view of one embodiment of a drugdelivery device, in accordance with the present disclosure.

FIG. 3 is a traverse cross-sectional view of one embodiment of a drugdelivery device, in accordance with the present disclosure.

FIG. 4 is a traverse cross-sectional view of one embodiment of a drugdelivery device, in accordance with the present disclosure.

FIG. 5 is a traverse cross-sectional view of one embodiment of a drugdelivery device, in accordance with the present disclosure.

FIG. 6 is a traverse cross-sectional view of one embodiment of a drugdelivery device, in accordance with the present disclosure.

FIG. 7A is a perspective view of another embodiment of a drug deliverydevice, without drug disposed therein or an elastic retention frame, ina relatively straightened shape, in accordance with the presentdisclosure.

FIG. 7B is a longitudinal cross-sectional view of the drug deliverydevice shown in FIG. 7A, taken along line 7B-7B.

FIG. 7C is a traverse cross-sectional view of the drug delivery deviceshown in FIG. 7A, taken along line 7C-7C.

FIG. 8A is a perspective view of another embodiment of a drug deliverydevice, without drug disposed therein or an elastic retention frame, ina relatively straightened shape, in accordance with the presentdisclosure.

FIG. 8B is a longitudinal cross-sectional view of the drug deliverydevice shown in FIG. 8A, taken along line 8B-8B.

FIG. 8C is a traverse cross-sectional view of the drug delivery deviceshown in FIG. 8A, taken along line 8C-8C.

FIG. 8D is a traverse cross-sectional view of the drug delivery deviceshown in FIG. 8A, taken along lines 8D-8D.

FIG. 9A is partial top plan view of another embodiment of a drugdelivery device, without any drug disposed therein, in a relativelystraightened shape, in accordance with the present disclosure.

FIG. 9B is a partial longitudinal cross-sectional view of the drugdelivery device shown in FIG. 9A, taken along line 9B-9B.

FIG. 10A is a perspective view of another embodiment of a drug deliverydevice, in accordance with the present disclosure.

FIG. 10B is a longitudinal cross-sectional view of the drug deliverydevice shown in FIG. 10A, taken along line 10B-10B.

FIG. 10C is a traverse cross-sectional view of the drug delivery deviceshown in FIG. 10A, taken along line 10C-10C.

FIG. 10D is a traverse cross-sectional view of the drug delivery deviceshown in FIG. 10A, taken along lines 10D-10D.

DETAILED DESCRIPTION

Improved implantable drug delivery devices, methods of manufacturing thesame, and methods of drug delivery are provided. In a particularembodiment, devices are configured for intravesical insertion andsustained drug delivery, preferably providing a zero order release rateof therapeutically effective amounts of the drug.

Diffusion-Based Drug Delivery Devices

It was discovered that it may be difficult to achieve a zero orderrelease rate beyond three to four days with osmotic pressure deliverymechanisms for certain drugs. In experiments, after three to four days,the drug release rate quickly decreased, which can cause the drug urineconcentration in the bladder to fall below a minimum effectiveconcentration before the end of treatment period. It is not alwaysfeasible to extend the period of zero order release simply by providingmore, or more densely packed, osmotic agent with the drugs, for exampledue to overall implant system size limitations. It is also not alwaysfeasible to instead provide overall first order drug release during anentire treatment period, because it may not be safe to have the initialpeak drug release rate high enough that even with the decay of the drugrelease rate toward the end of the treatment period, the release rate isstill above minimum effective concentration of the drug.

Accordingly, the particular devices described herein have beendeveloped, wherein instead of an osmotic drug release mechanism, drugrelease is controlled by drug diffusion through a drug-permeable polymeror matrix component defining part of the device housing. In oneembodiment, the device includes a drug-permeable polymer component orportion. For example, the drug-permeable component or portion of thedevice may be a portion of the housing formed of a material distinctfrom the remaining portion of housing (e.g., a strip or multiple stripsof material extending along at least a portion of the length of thehousing), such that the size, shape (e.g., arc angle), thickness, andmaterial properties of the drug-permeable wall structure may be selectedto achieve the desired drug release rate. In certain embodiments, thedrug permeable portion, the drug impermeable portion, or both the drugpermeable and impermeable portions are formed of polyurethanecompositions, to advantageously provide (i) controlled diffusion of thedrug from the device, (ii) desired mechanical properties (e.g.,compliancy), (iii) a device that may be thermally shape set to have adesired retention shape, and/or (iv) a device which may advantageouslybe manufactured in a coextrusion process.

In one aspect, as shown in FIGS. 1A and 1B, a drug delivery device 100is provided that includes a tubular housing having a closed drugreservoir lumen 106 bounded by a wall structure 104, wherein (i) atleast a portion of the wall structure 104 is water permeable, and (ii)at least a portion of the wall structure is permeable to the drug(contained in solid drug unit 108) such that the drug is releasable invivo by diffusion through the drug permeable portion of the wallstructure 104. In certain embodiments, as discussed in further detailbelow, the wall structure includes first and second wall structures thattogether form the housing. As used herein, the phrase “diffusion throughthe drug permeable portion” (e.g., through the “second wall structure,”the “second annular segment,” or another “drug permeable portion”)refers to the drug being released by passing through the wall bymolecular diffusion, and not by passing through an aperture or openstructure extending through that wall.

In one aspect, as shown in FIG. 2 , a drug delivery device 200 isprovided that includes a housing with a first wall structure 206 and asecond wall structure 205 that are adjacent one another and togetherform a tube defining a drug reservoir lumen 208, wherein (i) the secondwall structure 205, or both the first wall structure 206 and the secondwall structure 205, are permeable to water, and (ii) the first wallstructure 206 is impermeable to the drug and the second wall structure205 is permeable to the drug, such that the drug is releasable in vivoby diffusion through the second wall structure 205. As used herein, theterm “impermeable to the drug” refers to the wall being substantiallyimpermeable to the solubilized drug, such that no substantial amount ofthe solubilized drug can diffuse therethrough over the therapeuticperiod in which the device is located in vivo.

In certain embodiments, the tube is cylindrical or another suitableshape or design. As used herein, the term “cylindrical,” when used inreference to the tubular housing, refers to the housing having asubstantially cylindrical outer wall. In one embodiment, the device doesnot include an aperture; drug release is only by diffusion through thesecond wall structure.

In some embodiments, as shown in FIGS. 2 and 3 , the first wallstructure 206/306 and the second wall structure 205/305 are adjacent oneanother and together form a cylindrical tube. For example, such devicesmay be formed in a coextrusion process, such that the first and secondwall structures are integrally formed. In one embodiment, the coextrudedfirst and second wall structures are thermoplastic polymers possessingthe desired properties.

As shown in FIG. 3 , the first wall structure 306 and second wallstructure 306 together form a cylindrical tube having a lumen 308 inwhich a drug formulation is contained. The second wall structure 305 isin the form of a strip extending along at least a portion of the lengthof the first wall structure 306 and is permeable to the drug, while thefirst wall structure 306 is not permeable to the drug. In certainembodiments, multiple drug permeable strips may be used in a singledevice. Thus, the size, shape, thickness, and material properties of thesecond wall structure may be selected to achieve a desired drug releaserate.

In a preferred embodiment, as discussed in further detail below, thedevice is elastically deformable between a relatively straightened shapesuited for insertion through the urethra of a patient and into thepatient's bladder and a retention shape suited to retain the devicewithin the bladder. In one embodiment, as shown in FIGS. 7A-7C, 8A-8D,and 10A-10D, the device further includes retention frame lumen 734, 834,1034. In certain embodiments, the retention frame lumen includes anelastic wire, such a nitinol wire. In certain other embodiments, theretention frame lumen is filled with a shape set elastic polymer. Inother embodiments, as shown in FIGS. 1A-1B and 2-6 , the device does notinclude a retention frame lumen or a retention frame or wire. Instead,the material of the housing is configured to be elastically deformablebetween the straightened shape and the retention shape, in the absenceof a retention frame or wire. In certain embodiments, the tubularhousing is thermally shape set to have a coiled or other retentionshape. Thus, in such embodiments, the design and manufacturing of thedevice is simplified, and the overall size of the device is minimized(or drug payload may be increased if the size of the device remainsconstant). Advantageously, in embodiments without a retention frame, thetubular housing material serves the functions of (i) forming the drugreservoir lumen, (ii) controlling drug release, and (iii) retaining thedevice in the bladder upon deployment.

In one embodiment, as shown in FIGS. 7A-7C, a drug delivery device 700is provided that includes an elongated, elastic housing 702 having adrug reservoir lumen 704 extending between a first end 706 and a secondend 708. The elastic housing 702 is formed of a tubular wall structure710 that includes a first wall structure 716 and a second wall structure724 that are adjacent one another and together form a tube defining thedrug reservoir lumen 704, wherein (i) the second wall structure 724, orboth the first wall structure 716 and the second wall structure 724, arepermeable to water, and (ii) the first wall structure 716 is impermeableto the drug and the second wall structure 724 is permeable to the drug,such that the drug is releasable in vivo by diffusion through the secondwall structure 724.

In embodiments in which the first and second wall structures togetherform a cylindrical tube, any suitable end plugs or closures or thermallyformed seals may be used to seal the ends of the tube after the drug isloaded. These end plugs/closures ensure that the drug permeable polymerportions forming a portion of the external tube are the only path fordrug release.

In some embodiments, as shown in FIGS. 2 and 3 , the wall 206, 205/306,305 has a substantially constant thickness over its circumference. Forexample, the inner diameter 210/310 and outer diameter 212/312 of thefirst and second wall structures 206, 205/306, 305 (which together formthe cylindrical tube) are the same.

In other embodiments, the wall may have a varied thickness over thecircumference of the wall, for example as shown in FIGS. 4-6 , in whichthe drug permeable portion (405/505/605) has a thickness that is lessthan the thickness of the drug impermeable portion (406/506/606).Moreover, the thinner drug permeable wall structure (405/505/605) may bedisposed at various positions relative the adjacent, thicker drugimpermeable wall structure (406/506/606). As shown in FIG. 4 , thethinner drug permeable wall structure 405 may be flush with the innersurface of the drug impermeable wall structure 406 forming the drugreservoir lumen. As shown in FIG. 5 , the thinner drug permeable wall505 may be centered relative the thickness of the drug impermeable wallstructure 506. As shown in FIG. 6 , the thinner drug permeable wallstructure 605 may be flush with the outer surface of the drugimpermeable wall structure 606, opposite the surface forming the drugreservoir lumen.

That is, drug release is controlled by drug diffusion through adrug-permeable component defining a portion of the closed devicehousing. The drug-permeable wall structure may be located, dimensioned,and have material properties to provide the desired rate of controlleddrug diffusion from the device.

The particular material and arc angle of the drug permeable portion orwall structure can be selected to achieve a particular drug releaseprofile, i.e., water and drug permeation rates. For example, in certainembodiments, as shown in FIGS. 2 and 3 , the second wall structure205/305 comprises less than 90 percent of a cross sectional area of thetube, in a cross section normal to the longitudinal axis of the tube. Inone embodiment, the second wall structure comprises less than 50 percentof a cross sectional area of the tube, in a cross section normal to thelongitudinal axis of the tube. In one embodiment, the second wallstructure comprises less than 25 percent of a cross sectional area ofthe tube, in a cross section normal to the longitudinal axis of thetube.

In one embodiment, as shown in FIG. 2 , the second wall structure 205has an arc angle 214 of about 60 degrees of a circumference of thecylindrical tube 200 in the cross-section. In one embodiment, as shownin FIG. 3 , the second wall structure 305 has an arc angle 314 of about30 degrees of a circumference of the cylindrical tube 300 in thecross-section. In one embodiment, the second wall structure has an arcangle of about 10 degrees to about 170 degrees. In one embodiment, thesecond wall structure has an arc angle of about 15 degrees to about 90degrees. As used herein, the phrase “about” with reference to the arcangles of the second wall structure refers to the arc angle plus orminus 3 degrees. The second wall structure can be located on the innercurvature (0 degrees), the outer curvature (180 degrees), the top (90deg), or in-between when the device is formed to have a retention shapeas shown in FIG. 1 . The top (90 degree) location may be preferable whenthe second wall structure is formed of a material that significantlyswells once absorbing water.

In a second aspect, a drug delivery device having an elongated, elastichousing with a drug reservoir lumen extending between a first closed endand a second closed end has a tubular wall structure that includes afirst annular segment formed entirely of a first material which isimpermeable to the drug, and a second annular segment formed at leastpartially of a second material which is permeable to the drug andconfigured to release the drug in vivo by diffusion through the secondmaterial in the second annular segment, where the first annular segmenthas a first end which is integrally formed and connected with a firstend of the second annular segment. Such devices may overcome certainproblems associated with conventional extrusion processes. For example,in using certain conventional extrusion processes to make a tubulardevice body having two wall structures, the portion of the smaller wallstructure that includes the drug permeable material (which may bequantified by the arc angle defining the wall when viewed incross-section normal to the luminal axis) may only be decreased, ornarrowed, to a certain extent due to manufacturing limitations. It hasbeen discovered that this wall structure at the narrowest reliablymanufacturable arc angle may still yield too large an area for drugdiffusion (i.e., drug is released too fast) for certain drugs in adevice of a given length. Many other variables or device specificationsmay be considered for modifying the drug release kinetics in such asituation; however, changing those variables may also undesirably altermechanical, tolerability, available drug payload volume, or otherdesired characteristics of the device. It was therefore discovered thatan extrusion process may be modified so that the drug permeable materialneed not extend the full length of the device body. That is, theextrusion process can be modified to implement a discontinuous (orintermittent) feed of the drug permeable material during the process ofextruding the drug impermeable wall material of the device body. In thisway, the overall dimensions of the tube structure can be maintained, yetadvantageously both the length and width of the diffusion portion of thedevice wall structure can be controlled to give a selected area of, andthus rate for, diffusion of drug for release.

Accordingly, tubular devices have been developed which are designed toreduce or control drug release rates without negatively altering themechanical properties and suitable dimensions for device deployment andtolerability. In embodiments, the designs reduce drug release rates byreducing the length of the drug permeable regions(s) such that thelength runs along only a portion of the overall length of the device.Advantageously, larger arc angles of the drug permeable region(s) cantherefore be employed to reduce drug release rates from the device.Additionally, by decreasing the length of the drug permeable region, alesser amount of drug permeable material, compared to conventionaldevices, may be used to effect a reduced drug release rate. This isbeneficial for the mechanical properties of the device, particularlywhen the device is used in the bladder.

In one embodiment, as shown in FIGS. 8A-8D, a drug delivery device 800is provided that includes an elongated, elastic housing 802 having adrug reservoir lumen 804 extending between a first end 806 and a secondend 808. The elastic housing 802 is formed of a tubular wall structure810 that includes a first annular segment 812 and a second annularsegment 814. In a preferred embodiment, the first and second annularsegments 812, 814 are formed together in an extrusion process.

The first annular segment 812 is formed entirely of a first material 816which is impermeable to the drug (not shown) disposed in the drugreservoir lumen 804. The first annular segment 812 has a first end 818which is integrally formed and connected with a first end 820 of thesecond annular segment 814. The second annular segment 814 is formed ofthe first material 816 and a second material 824 which is permeable tothe drug disposed in the drug reservoir lumen 804, such that the drug isreleasable in vivo by diffusion through the second material 824.

In the embodiment illustrated in FIGS. 8A-8D, the second annular segment814 includes a central portion 826 that extends between an externalsurface 828 and an internal surface 830 of the tubular wall structure810. The central portion 826 is formed entirely of the second material824.

The particular material and arc angle of the second material within thesecond annular segment can be selected to achieve a particular drugrelease profile, i.e., water and drug permeation rates, as discussedabove with reference to the drug permeable second wall structure withinthe devices having a drug permeable portion extending along their length(e.g., as shown in FIGS. 7A-7C). For example, in certain embodiments,the portion of the second annular segment comprising the second materialcomprises less than about 25% of a cross sectional area of the tubularwall structure taken at the central portion. In one embodiment, theportion of the second annular segment comprising the first materialforms a first arcuate portion and the portion of the second annularsegment comprising the second material forms a second arcuate portionhaving an arc angle of about 15 degrees to about 120 degrees of acircumference of the tubular wall structure. The first and secondarcuate portions are integrally connected and together define theannulus of the second annular segment. In one embodiment, the portion ofthe second annular segment comprising the second material has an arcangle of about 30 degrees to about 60 degrees.

Once the drug is loaded into the drug reservoir lumen 804, any suitableend plugs or closures or thermally formed seals may be used toseal/close the first and second ends 806, 808 of the elastic housing802. These end plugs/closures ensure that the second material forming aportion of the elastic housing is the sole path for drug release.

In certain embodiments, as illustrated in FIGS. 8A-8D, the tubular wallstructure further includes a third annular segment 832, which isintegrally formed and connected with an opposed second end 822 of thesecond annular segment 814. In one embodiment, the second and thirdannular segments 814, 832 are formed together in an extrusion process.In one embodiment, the third annular segment 832 is formed entirely ofthe first material 816.

FIGS. 9A-9B illustrate a variation of the drug delivery device 800 shownin in FIGS. 8A-8D, with FIGS. 9A-9B showing only partial longitudinalplan and cross-sectional views of the device 900. The drug deliverydevice 900 includes an elongated, elastic housing 902 formed of atubular wall structure. The tubular wall structure includes a firstannular segment 912, a second annular segment 914, and a third annularsegment 932. The first annular segment is formed of a first material916, the second annular segment 914 is formed of the first material 916and a second material 924, and the third annular segment 932 is formedof the first material 916.

In this embodiment, the second annular segment 914 includes a centralportion 926 that extends between an external surface 928 and an internalsurface 930 of the tubular wall structure 910. The central portion 926is formed entirely of the second material 924. The second annularsegment 914 is shown to include a transition region leading to each ofthe first and third annular segments 912, 932. In this way, not all ofthe second material 924 within the second annular segment 914 extendsfrom the external and internal surfaces 928, 930 of the tubular wallstructure. The interfaces formed by 918, which is an end of 912, and920, which is an end of 914, can be angled or straight.

In some embodiments, the tubular wall structure includes one or moreadditional annular segments that comprise the second material or anothermaterial that is permeable to the drug. For example, in one embodiment,the tubular wall structure comprises an additional annular segment,which is integrally formed and connected with an opposed second end ofthe second annular segment. In one embodiment where the tubular wallstructure includes the third annular segment that is connected with anopposed second end of the second annular segment, the tubular wallstructure comprises an additional annular segment, which is integrallyformed and connected with the opposing freed end of the third annularsegment.

In an alternative embodiment, the second material of the device isomitted, such that the absence of the second material defines one ormore apertures in the tubular wall structure. Depending on the extrusionprocess, such an aperture may be substantially round, square, orrectangular, or a slit. Drug release may occur by diffusion through theaperture, or if small enough, drug release from the device may occur byosmotic pressure.

Another embodiment of a drug delivery device is shown in FIGS. 10A-10D.The drug delivery device 1000 includes an elongated, elastic housing1002 having a drug reservoir lumen 1004 extending between a first end1006 and a second end 1008. The elastic housing 1002 is formed of atubular wall structure 1010 that includes a first annular segment 1012and a second annular segment 1014. In a preferred embodiment, the firstand second annular segments 1012, 1014 are formed together in anextrusion process.

The first annular segment 1012 is formed entirely of a first material1016 which is impermeable to the drug disposed in the drug reservoirlumen 1004. The first annular segment 1012 has a first end 1018 which isintegrally formed and connected with a first end 1020 of the secondannular segment 1014. The second annular segment 1014 is formedprimarily or exclusively of the second material 1024 which is permeableto the drug disposed in the drug reservoir lumen 1004, such that thedrug is releasable in vivo by diffusion through the second material1024. The second annular segment may include a transition region, suchthat the second annular segment is formed exclusively of the secondmaterial in a central part, and formed of a graduated combination of thefirst and second materials in a transition region at opposed ends aboutthe central part.

Once the drug is loaded into the drug reservoir lumen 1004, any suitableend plugs or closures or thermally formed seals may be used toseal/close the first and second ends 1006, 1008 of the elastic housing1002. These end plugs/closures ensure that the second material forming aportion of the elastic housing is the only path for drug release.

In certain embodiments, as illustrated in FIGS. 10A-10D, the tubularwall structure 1010 further includes a third annular segment 1032, whichis integrally formed and connected with an opposed second end 1022 ofthe second annular segment 1014. In one embodiment, the second and thirdannular segments 1014, 1032 are formed together in an extrusion process.In one embodiment, the third annular segment 1032 is formed entirely ofthe first material 1016.

In a variation of the foregoing illustrated embodiments, an aperture orslit is provided in a drug-impermeable wall structure (e.g., in thefirst annular segment), in a drug-permeable wall structure (e.g., in thesecond annular segment), or in at least one end plug closing off thedrug reservoir lumen. In such an embodiment, drug release in vivo occursby both (trans-wall) diffusion and osmosis. The osmotic releasecontribution through a hole or a slit may not be significant if the drughas a relatively low solubility. However, the hole or slit can serve asa pressure relief vent that can prevent unwanted swelling of theextruded housing.

In embodiments, the length (L) of the second annular segment is lessthan the total length (L_(T)) of the elastic housing. This beneficiallymaintains a drug release rate provided by a conventional device orreduces the drug release rate by increasing the arc angle of the secondmaterial without increasing the length of the device. In fact, incertain embodiments, the total length of the device can be decreased,while still having a low or reduced drug release rate.

In one embodiment, the length of the second annular segment is fromabout 5% to about 50% of the length of the elastic body. In anotherembodiment, the length of the second annular segment is from about 10%to about 30% of the length of the elastic body. In one embodiment, thelength ratio of the second annular segment to the elastic body is lessthan about 0.1. In another embodiment, the length ratio of the secondannular segment to the elastic body is less than about 0.4. As usedherein, the phrase “about” with reference to lengths refers to thelength plus or minus 10 percent of the recited value. In one embodiment,the length of the second annular segment is from about 1 cm to about 8cm.

Unless otherwise noted, as used herein, the length of a particularelement is the longitudinal distance such element extends between itsopposing ends. For example, in one embodiment, the length of eachannular segment is the longitudinal distance between its first andsecond opposing ends. For example, in one embodiment, the length of theelastic body is the length between its opposed first and second ends.

In the foregoing embodiments, the first material or the first wallstructure, the second material or the first wall structure, or both, isformed of a water permeable material. In a preferred embodiment, thedrug is in a solid form (e.g., a tablet or plurality of tablets) and atleast a portion of the tubular body is water permeable to permit in vivosolubilization of the drug while in the drug reservoir lumen. Inembodiments, the first material or first wall structure may be the onlywater permeable portion. In other embodiments both the first and secondmaterials/wall structures may be water permeable.

The material(s) for the wall structures and/or annular segments of thepresent devices can be selected from a variety of suitable materials,for example silicone, polyurethane, ethylene-vinyl acetate (EVA),thermoplastic silicone polyether polyurethane, aliphatic thermoplasticsilicone polyether polyurethane, segmented polyether polyurethane,thermoplastic polyether polyurethane, thermoplastic polycarbonatepolyurethane, Bionate®PCU, BioSpan® SPU, CarboSil®TSPCU, Elasthane™ TPU,PurSil®TSPU (DSM), other thermoplastic polyurethanes (TPUs), includingaliphatic and aromatic, polycarbonate-based thermoplastic polyurethanes,such as Carbothane™ TPU, Tecoflex™ TPU, Tecothane™ TPU, Tecothane™ SoftTPU, Pellethane®TPU, and Tecophilic™ TPU, and combinations or blendsthereof.

The second material or wall structure, or other material that ispermeable to the drug contained in the drug reservoir, may be ahydrophilic polymer, for example hydrophilic polyurethane, hydrophilicpolyesters, and hydrophilic polyamides. In one embodiment, the drugpermeable wall structure is Tecophilic™ TPU, HydroThane™ TPU(AdvanSource Biomaterials Corp.), Quadraphilic™ TPU (Biomerics, LLC)(ALC grades are aliphatic polycarbonate-based and ALE grades arealiphatic polyether-based hydrophilic polyurethanes), HydroMed™(AdvanSource Biomaterials Corp.), or Dryflex® (HEXPOLTPE). Anotherhydrophilic polymer that may form the drug permeable portion(s) or wallstructure(s) is polyether block amide Pebax® MV 1074 SA 01 MED (Arkema),which is a thermoplastic elastomer made of flexible and hydrophilicpolyether and rigid polyamide.

In certain embodiments, the first material and/or second material or thefirst wall structure and/or second wall structure include at least onethermoplastic material. In certain embodiments, the first material orfirst wall structure, the second material or second wall structure, orboth, comprise a polyurethane composition, such as a thermoplasticpolyurethane. In certain embodiments, the first wall structure/materialcomprises a first polyurethane composition and the second wallstructure/material comprises a second polyurethane composition, which isdifferent from the first polyurethane composition.

In one embodiment, the first material or first wall structure is formedfrom Tecoflex™ (e.g., EG-80A), Tecothane™ Soft (e.g., AR-62A),Carbothane™ TPU (e.g., AC-4075A and PC-3575A), or a combination or blendthereof, and the second material or second wall structure is formed fromTecophilic™ TPU (e.g., HP-60D-20, HP-60D-35, HP-60D-60, and HP-93A-100),another hydrophilic TPU, or a combination or blend thereof.

In one embodiment, an inner diameter of the cylindrical tube may be fromabout 1.0 mm to about 2.5 mm. In one embodiment, an outer diameter ofthe cylindrical tube is from about 2.0 mm to about 4.1 mm. In oneembodiment, a thickness of the first wall structure, the second wallstructure, or both, is from about 0.2 mm to about 1.0 mm. In certainembodiments, the thickness of the second wall structure is differentthan the thickness of the first wall structure.

Thus, as compared to drug delivery systems utilizing a homogenousmaterial (e.g., a blend of permeable and impermeable thermoplasticmaterials) to form a drug permeable tube, the mechanical properties of atube utilizing the dual wall structure (e.g., the drug permeable stripembodiments) advantageously can be decoupled from the drug release(e.g., diffusion) properties of the tube. For example, in a singlematerial tube, changing the material of tube inherently affects both themechanical and diffusion properties of the device. Moreover, the drugrelease properties of a blended polymer may not be readily predictable.In addition, it is often challenging to achieve a truly homogeneousblend when mixing two thermoplastics. Thus, it requires experimentationto modulate drug release rate with such a tubular drug delivery system.

For use in the bladder, it is important that the device be compliant(i.e., easily flexed, soft feeling) during detrusor muscle contractionin order to avoid or mitigate discomfort and irritation to the patient.Thus, it is noted the durometer of the first and second materials ofconstruction are important, and the proportion of a high durometermaterial may be limited in constructing a device housing of a given sizewhile keeping it suitably compliant in the bladder. For example,Tecophilic™ thermoplastic polyurethane (Lubrizol Corp.) may have a Shorehardness greater than 70 A, such as from 80 A to 65 D, while other drugimpermeable thermoplastic polyurethanes may have a Shore hardness thatis less than or greater than Tecophilic™, such as less than 90 A.Accordingly, it can be advantageous to utilize a combination of twodifferent polymeric materials, rather than making the device entirely ofthe water-swelling hydrophilic, drug-permeable second material, toachieve desired mechanical properties of the tube.

In one embodiment, the first material or first wall structure has aShore durometer value from about 50 A to about 70 A. In one embodiment,the first material or first wall structure has a Shore durometer valueof less than 90 A. In certain embodiments, the second material or secondwall structure has a Shore durometer value from about 70 A to about 65D. The particular material and its thickness and wall area, e.g., arcangle, can be selected to achieve a particular drug release profile,i.e., water and drug permeation rates.

In one embodiment, the first and second materials/wall structures eachcomprise a thermoplastic polyurethane, the tubular wall structure iselastically deformable from a retention shape suited to retain thedevice within the bladder to a relatively straightened shape suited forinsertion through a lumen into the bladder, and the tubular wallstructure is thermally shaped to have the retention shape.

In embodiments where the drug impermeable portion takes up the majorityof the tube cross-sectional area and is significantly permeable to water(e.g., Tecoflex EG-80 A) and the tubing has an orifice, the system canbe operated to release the drug via both diffusion and osmosis, as longas the reservoir contents (e.g., API and excipients) can create anosmotic pressure gradient across the tubing wall. Thus, the presence ofthe osmotic orifice can help reduce possible swelling of the reservoirdue to osmotic pressure.

In preferred embodiments, the devices described herein are configured torelease a therapeutically effective amount of the drug, where the rateof the release of the drug from the drug delivery device is zero orderover at least 36 hours. In one embodiment, the rate of the release ofthe drug from the drug delivery device is essentially zero order over atleast 7 days. In embodiments, the device is configured to release atherapeutically effective amount of the drug over a period from 3 daysto 90 days, e.g., from 7 days to 30 days, or from 7 days to 14 days.Desirably, the rate of the release of the drug from the drug deliverydevice is zero order over at least 7 days, e.g., from 7 to 14 days, orlonger. In certain embodiments, the device is configured to beginrelease of the drug after a lag time, for example due to a void space inthe inner washer. In certain embodiments, the lag time may at leastabout 30 minutes, from about 12 hours to about 24 hours, or up to about2 days.

In preferred embodiments, the drugs are gemcitabine hydrochloride andtrospium chloride. In one embodiment, at least 25 mg/day of gemcitabineis released over 7 days. In another embodiment, at least 1 mg/day oftrospium chloride is released over 7 days to 3 months. In otherembodiments, as discussed in more detail herein, other drugs can bedelivered with the devices described herein.

Other Aspects of the Drug Delivery Devices

The devices and methods disclosed herein build upon those described inU.S. Pat. Nos. 8,182,464 and 8,343,516, as well as in U.S. ApplicationPublication No. 2009/0149833 (MIT 12988); U.S. Application PublicationNo. 2010/0331770 (TB 101); U.S. Application Publication No. 2010/0060309(TB 108); U.S. Application Publication No. 2011/0202036 (TB 107); U.S.Application Publication No. 2011/0152839 (TB 112); PCT/US11/46843, filedAug. 5, 2011 (TB 113); U.S. application Ser. No. 13/267,560, filed Oct.6, 2011 (TB 116); and U.S. application Ser. No. 13/267,469, filed Oct.6, 2011 (TB 117), each of which is incorporated herein by reference.

In certain embodiments, the devices are configured for intravesicalinsertion and retention in a patient. For example, the devices can beelastically deformable between a relatively straightened shape suitedfor insertion through a lumen into a body cavity of a patient and aretention shape suited to retain the device within the body cavity, suchas shown in FIG. 1A. When in the retention shape after deployment in thebladder, for example, the devices may resist excretion in response tothe forces of urination or other forces. Since the devices are designedto be retained within a lumen or body cavity, they are capable ofovercoming some of the deficiencies of conventional treatments, such asthose related to the bladder. The devices described herein can beinserted once and release drug over a desired period of time withoutsurgery or frequent interventions. The devices, as a result, may reducethe opportunity for infection and side effects, increase the amount ofdrug delivered locally or regionally to the bladder, or improve thequality of life of the patient during the treatment process. After drugrelease, the devices can be removed, for example by cystoscope andforceps, or be bioerodible, at least in part, to avoid a retrievalprocedure.

The device may be loaded with at least one drug in the form of one ormore solid drug units, such as tablets, capsules, or pellets. Providingone or more drugs in solid form to a patient is often advantageous.Solid drugs can provide a relatively large drug payload volume to totaldevice volume and potentially enhance stability of the drugs duringshipping, storage, before use, or before drug release. Solid drugs,however, should be solubilizable in vivo in order to diffuse intothrough the drug-permeable component and into the patient's surroundingtissues in a therapeutically effective amount.

The drug reservoir lumen may hold one or several drug tablets or othersolid drug units. In one embodiment, the device holds from about 10 to100 cylindrical drug tablets, such as mini-tablets, among a number ofdiscrete drug reservoir lumens. In certain embodiments, the mini-tabletsmay each have a diameter of about 1.0 to about 3.3 mm, such as about 1.5to about 3.1 mm, and a length of about 1.5 to about 4.7 mm, such asabout 2.0 to about 4.5 mm.

The devices may be inserted into a patient using a cystoscope orcatheter. Typically, a cystoscope for an adult human has an outerdiameter of about 5 mm and a working channel having an inner diameter ofabout 2.4 mm to about 2.6 mm. In embodiments, a cystoscope may have aworking channel with a larger inner diameter, such as an inner diameterof 4 mm or more. Thus, the device may be relatively small in size. Forexample, when the device is elastically deformed to the relativelystraightened shape, the device for an adult patient may have a totalouter diameter that is less than about 2.6 mm, such as between about 2.0mm and about 2.4 mm. For pediatric patients, the dimensions of thedevice are anticipated to be smaller, e.g., proportional for examplebased on the anatomical size differences and/or on the drug dosagedifferences between the adult and pediatric patients. In addition topermitting insertion, the relatively small size of the device may alsoreduce patient discomfort and trauma to the bladder.

In one embodiment, the overall configuration of the device promotes invivo tolerability for most patients. In a particular embodiment, thedevice is configured for tolerability based on bladder characteristicsand design considerations described in U.S. Application Publication No.2011/0152839 (TB 112), which is incorporated herein by reference.

Within the three-dimensional space occupied by the device in theretention shape, the maximum dimension of the device in any directionpreferably is less than 10 cm, the approximate diameter of the bladderwhen filled. In some embodiments, the maximum dimension of the device inany direction may be less than about 9 cm, such as about 8 cm, 7 cm, 6cm, 5 cm, 4.5 cm, 4 cm, 3.5 cm, 3 cm, 2.5 or smaller. In particularembodiments, the maximum dimension of the device in any direction isless than about 7 cm, such as about 6 cm, 5 cm, 4.5 cm, 4 cm, 3.5 cm, 3cm, 2.5 cm or smaller. In preferred embodiments, the maximum dimensionof the device in any direction is less than about 6 cm, such as about 5cm, 4.5 cm, 4 cm, 3.5 cm, 3 cm, 2.5 cm or smaller. More particularly,the three-dimension space occupied by the device is defined by threeperpendicular directions. Along one of these directions the device hasits maximum dimension, and along the two other directions the device mayhave smaller dimensions. For example, the smaller dimensions in the twoother directions may be less than about 4 cm, such as about 3.5 cm, 3cm, 2.5 cm or less. In a preferred embodiment, the device has adimension in at least one of these directions that is less than 3 cm.

In some embodiments, the device may have a different dimension in atleast two of the three directions, and in some cases in each of thethree directions, so that the device is non-uniform in shape. Due to thenon-uniform shape, the device may be able to achieve an orientation ofreduced compression in the empty bladder, which also is non-uniform inshape. In other words, a particular orientation of the device in theempty bladder may allow the device to exert less contact pressureagainst the bladder wall, making the device more tolerable for thepatient.

The overall shape of the device may enable the device to reorient itselfwithin the bladder to reduce its engagement or contact with the bladderwall. For example, the overall exterior shape of the device may becurved, and all or a majority of the exterior or exposed surfaces of thedevice may be substantially rounded. The device also may besubstantially devoid of sharp edges, and is exterior surfaces may beformed from a material that experiences reduced frictional engagementwith the bladder wall. Such a configuration may enable the device toreposition itself within the empty bladder so that the device applieslower contact pressures to the bladder wall. In other words, the devicemay slip or roll against the bladder wall into a lower energy position,meaning a position in which the device experiences less compression.

In one embodiment, the device is generally planar in shape even thoughthe device occupies three-dimensional space. Such a device may define aminor axis, about which the device is substantially symmetrical, and amajor axis that is substantially perpendicular to the minor axis. Thedevice may have a maximum dimension in the direction of the major axisthat does not exceed about 6 cm, and in particular embodiments is lessthan 5 cm, such as about 4.5 cm, about 4 cm, about 3.5 cm, about 3 cm,or smaller. The device may have a maximum dimension in the direction ofthe minor axis that does not exceed about 4.5 cm, and in particularembodiments is less than 4 cm, such as about 3.5 cm, about 3 cm, orsmaller. The device is curved about substantially its entire exteriorperimeter in both a major cross-sectional plane and a minorcross-sectional plane. In other words, the overall exterior shape of thedevice is curved and the cross-sectional shape of the device is rounded.Thus, the device is substantially devoid of edges, except for edges onthe two flat ends, which are completely protected within the interior ofthe device when the device lies in a plane. These characteristics enablethe device to reorient itself into a position of reduced compressionwhen in the empty bladder.

The device also may be small enough in the retention shape to permitintravesical mobility. In particular, the device when deployed may besmall enough to move within the bladder, such as to move freely orunimpeded throughout the entire bladder under most conditions of bladderfullness, facilitating patient tolerance of the device. Free movement ofthe device also facilitates uniform drug delivery throughout the entirebladder.

The device also may be configured to facilitate buoyancy, such as withthe use of low density materials of construction for the housingcomponents and/or by incorporating gas or gas generating materials intothe housing, as described for example in U.S. Application PublicationNo. 2012/0089121 (TB 116), which is incorporated herein by reference. Ingeneral, the device in the dry and drug-loaded state may have a densityin the range of about 0.5 g/mL to about 1.5 g/mL, such as between about0.7 g/mL to about 1.3 g/mL. In some embodiments, the device in the dryand drug-loaded state has a density that is less than 1 g/mL.

The implantable drug delivery device can be made to be completely orpartially bioerodible so that no explanation, or retrieval, of thedevice is required following release of the drug formulation. In someembodiments, the device is partially bioerodible so that the device,upon partial erosion, breaks into non-erodible pieces small enough to beexcreted from the bladder. As used herein, the term “bioerodible” meansthat the device, or part thereof, degrades in vivo by dissolution,enzymatic hydrolysis, erosion, resorption, or combinations thereof. Inone embodiment, this degradation occurs at a time that does notinterfere with the intended kinetics of release of the drug from thedevice. For example, substantial erosion of the device may not occuruntil after the drug formulation is substantially or completelyreleased. In another embodiment, the device is erodible and the releaseof the drug formulation is controlled at least in part by thedegradation or erosion characteristics of the erodible device body. Thedevices described herein may be designed to conform with thecharacteristics of those described in U.S. Application Publication No.2012/0089122 (TB 117), which is incorporated herein by reference.

The drug delivery device may be sterilized before being inserted into apatient. In one embodiment, the device is sterilized using a suitableprocess such as gamma irradiation or ethylene oxide sterilization,although other sterilization processes may be used.

Retention of the Device in a Body Cavity

The devices described herein are elastically deformable between arelatively straightened or uncoiled shape suited for insertion through alumen into the bladder (or other body cavity) of a patient and aretention or coiled shape suited to retain the device within the urinarybladder (or other body cavity). In certain embodiments, the drugdelivery device may naturally assume the retention shape and may bedeformed, either manually or with the aid of an external apparatus, intothe relatively straightened shape for insertion into the body. Oncedeployed the device may spontaneously or naturally return to theinitial, retention shape for retention in the body.

For the purposes of this disclosure, the term “retention shape”generally denotes any shape suited for retaining the device in theintended implantation location, including, but not limited to, a coiledor “pretzel” shape, such as shown in FIG. 1A, which is suited forretaining the device in the bladder. Similarly, the term “relativelystraightened shape” generally denotes any shape suited for deploying thedrug delivery device into the body, including, but not limited to, alinear or elongated shape, such as shown in FIGS. 7A, 8A, 10A, which issuited for deploying the device through the working channel of catheter,cystoscope, or other deployment instrument positioned in a lumen of thebody, such as the urethra.

In some embodiments, as shown in FIGS. 7A-7C, 8A-8D, and 10A-10D, thedevice further includes retention frame lumen 734, 834, 1034 and aretention frame (not shown) positioned in the retention frame lumen. Forexample, the retention frame lumen and retention frame may be asdescribed in U.S. Application Publication No. 2010/0331770 (TB 101);U.S. Application Publication No. 2010/0060309 (TB 108); U.S. ApplicationPublication No. 2011/0202036 (TB 107); and U.S. Application PublicationNo. 2011/0152839 (TB 112).

In other embodiments, as shown in FIGS. 1A-1B and 2-6 , the device doesnot include a retention frame lumen or a retention frame or wire.Instead, the material of the housing is configured to be elasticallydeformable between the straightened shape and the retention shape, inthe absence of a retention frame or wire. In such embodiments, thedesign and manufacturing of the device is simplified, and the overallsize of the device is minimized (or drug payload may be increased wherethe size of the device remains constant). Advantageously, in embodimentswithout a retention frame, the tubular housing material serves thefunctions of (i) forming the drug reservoir lumen, (ii) controlling drugrelease, and (iii) retaining the device in the bladder upon deployment.

For example, the tubular housing may be thermally shape set to have theretention shape. Thus, the housing may comprise one or morethermoplastic materials that are suitable to be thermally formed intothe retention shape. In certain embodiments, a drug delivery deviceincludes a tubular housing having a closed drug reservoir lumen boundedby a wall structure comprising at least one thermoplastic material,wherein (i) at least a portion of the wall structure is water permeableand at least a portion of the wall structure is drug permeable, (ii) thetubular housing is elastically deformable from a retention shape suitedto retain the device within the bladder to a relatively straightenedshape suited for insertion through a lumen into the bladder, and (iii)the tubular wall is thermally shaped to have the retention shape.

In certain embodiments where the wall structure comprises first andsecond wall structures or first and second annular segments, the firstand second wall structures/segments are each a thermoplasticpolyurethane and the tubular housing is thermally shaped to have theretention shape. In one embodiment, the tubular wall has a springconstant effective to impede the device from assuming the relativelystraightened shape once implanted in the bladder. Thus, the propertiesof the tubular wall may cause the device to function as a spring,deforming in response to a compressive load but spontaneously returningto its initial shape once the load is removed.

In certain embodiments, the devices may naturally assume the retentionshape, may be deformed into the relatively straightened shape, and mayspontaneously return to the retention shape upon insertion into thebody. The tubular wall structure in the retention shape may be shapedfor retention in a body cavity, and in the relatively straightened shapemay be shaped for insertion into the body through the working channel ofa deployment instrument such as a catheter or cystoscope. To achievesuch a result, the tubular wall structure may have an elastic limit,modulus, and/or spring constant selected to impede the device fromassuming the relatively lower-profile shape once implanted. Such aconfiguration may limit or prevent accidental expulsion of the devicefrom the body under expected forces. For example, the device may beretained in the bladder during urination or contraction of the detrusormuscle.

In a preferred embodiment, the device is elastically deformable betweena relatively straightened shape suited for insertion through a catheteror cystoscope extending through a patient's urethra of a patient and acurved or coiled shape suited to retain the device within the bladder(i.e., to prevent its expulsion from the bladder during urination)following release of the device from the end of the catheter orcystoscope.

As shown in FIG. 1A, the retention shape may include a coiled or“pretzel” shape. The pretzel shape essentially comprises at least twosub-circles, each having its own smaller arch and sharing a commonlarger arch. When the pretzel shape is first compressed, the larger archabsorbs the majority of the compressive force and begins deforming, butwith continued compression the smaller arches overlap, and subsequently,all three of the arches resist the compressive force. The resistance tocompression of the device as a whole increases once the two sub-circlesoverlap, impeding collapse and voiding of the device as the bladdercontracts during urination.

The wall structure in the retention shape may have a two-dimensionalstructure that is confined to a plane, a three-dimensional structure,such as a structure that occupies the interior of a spheroid, or somecombination thereof. The retention shape may comprise one or more loops,curls, or sub-circles, connected either linearly or radially, turning inthe same or in alternating directions, and overlapping or notoverlapping. The retention shape may comprise one or more circles orovals arranged in a two-dimensional or a three-dimensionalconfiguration, the circles or ovals may be either closed or opened,having the same or different sizes, overlapping or not overlapping, andjoined together at one or more connecting points. The retention shapealso may be a three-dimensional structure that is shaped to occupy orwind about a spheroid-shaped space, such as a spherical space, a spacehaving a prorate spheroid shape, or a space having an oblate spheroidshape. The wall structure in the retention shape may be shaped to occupyor wind about a spherical space. The wall structure in the retentionshape may generally take the shape of two intersecting circles lying indifferent planes, two intersecting circles lying in different planeswith inwardly curled ends, three intersecting circles lying in differentplanes, or a spherical spiral. In each of these examples, the wallstructure can be stretched to the linear shape for deployment through adeployment instrument. The wall structure may wind about or through thespherical space, or other spheroid-shaped space, in a variety of othermanners. Examples of alternative configurations are described in theU.S. patent applications incorporated by reference herein.

Advantageously, drug delivery devices utilizing thermally formedcoextruded tubing with drug permeable and drug impermeable portionsintegrate three functional components (drug reservoir/housing, drugpermeation route, and retentive feature) into a single thermally shapedco-extruded tubing component, which simplifies the device design and theability to control the drug release rate. As discussed herein, in suchdevices, the drug release rate can be relatively easily modified bycontrolling the angle and thickness of the drug permeable portion (e.g.,strip) without changing whole tube housing material.

A thermally shaped coextruded tubular housing may be loaded with drugtablets and both ends may be sealed thermally or with adhesive (such asTecoflex 1-MP TPU Adhesive, Lubrizol). If the local tube cross-sectiondeformation or tube kinking occurs, the tablet loading will bedifficult. Therefore, the tube dimensions should be chosen to preventkinking when the tube is thermally shaped. The critical bending radiusof curvature (R*) of elastic tubes under pure bending condition can beapproximated using the following equation:

$R^{*} \approx {\frac{3}{\sqrt{2}}\frac{r^{2}\sqrt{1 - v^{2}}}{w}}$

where v is Poisson's ratio, r is the mean radius (i.e. (ID+OD)/4), and wis the tube wall thickness (Guarracino, F. 2003. On the analysis ofcylindrical tubes under flexure: theoretical formulation, experimentaldata and finite element analyses. Thin Wall Struct; 41:127-147). As anillustration, FIG. 6 is a multi-coiled polyurethane tube with 2.16 mminner diameter and 0.81 mm wall thickness. With a Poisson's ratio v of0.49 for polyurethanes (H. J. Qia, M. C. Boyce, Stress-strain behaviorof thermoplastic polyurethanes, 2005 Mechanics of Materials;37(8):817-839), the estimated critical radius is 0.5 cm. Therefore, whenthermally shaping a polyurethane tube, the radius of curvature should beabove 0.5 cm all along the length of the tube to prevent kinking. Thus,in one embodiment, the retention shape comprises at least one loophaving a radius of curvature of at least 0.5 cm.

The Drug Formulation and Solid Drug Tablets

The drug reservoir lumen may contain a drug in various forms, includingsolids, semi-solids, liquids, suspensions, gels, etc. In a preferredembodiment, as shown in FIGS. 1A and 1B, a drug formulation is formedinto solid drug units 108 that are loaded into the drug reservoir lumen106 of the device 100. Each of the solid drug units is a solid, discreteobject that substantially retains a selectively imparted shape (at thetemperature and pressure conditions to which the delivery devicenormally will be exposed during assembly, storage, and handling beforeimplantation). The drug units may be in the form of tablets, capsules,pellets, or beads, although other configurations are possible.

The solid drug units can be formed using a stable and scalablemanufacturing process. Particularly, the drug tablets are sized andshaped for loading into and efficiently storing the tablets in a housingof a drug delivery device that can be deployed into the bladder oranother cavity, lumen, or tissue site in a patient in a minimallyinvasive manner.

The solid drug units may be made by a direct powder compaction ortableting process, a molding process, or other processes known in thepharmaceutical arts. Suitable drug tablet forming methods are describedin U.S. Application Publication No. 2010/0330149 (TB 102), which isincorporated herein by reference. The drug formulation also may beloaded into the device housing in workable form and may cure therein.For example, in embodiments in which the drug formulation is configuredto be melted and solidified, the drug formulation can be melted,injected into the device housing in melted form and then solidified. Thedrug formulation also may be extruded with the device housing, may curewithin the housing, and subsequently may be cut in spaced positionsalong the length of the housing to form segments with exposed surfaceareas of drug.

The solid drug unit includes a drug formulation, which includes a drugcontent and may include an excipient content. In a preferred embodiment,the drug content includes one or more drugs, or active pharmaceuticalingredients (API), while the excipient content includes one or morepharmaceutically acceptable excipients. The drug formulation can includeessentially any therapeutic, prophylactic, or diagnostic agent, such asone that would be useful to deliver locally to a body cavity or lumen orregionally about the body cavity or lumen. The drug formulation mayconsist only of the API, or one or more excipients may be included.

As used herein, the term “drug” with reference to any specific drugdescribed herein includes its alternative forms, such as salt forms,free acid forms, free base forms, and hydrates. The term “excipient” isknown in the art, and representative examples of excipients useful inthe present drug units may include ingredients such as binders,lubricants, glidants, disintegrants, colors, fillers, diluents,coatings, or preservatives, as well as other non-active ingredients tofacilitate manufacturing, stability, dispersibility, wettability, and/orrelease kinetics of the drug or administering the drug unit. The drugmay be small molecule, macromolecule, biologic, or metabolite, amongother forms/types of active ingredients.

In order to maximize the amount of drug that can be stored in andreleased from a given drug delivery device of a selected (small) size,the drug unit preferably comprises a high weight fraction of drug orAPI, with a reduced or low weight fraction of excipients as are requiredfor solid drug unit manufacturing and device assembly and useconsiderations. For the purposes of this disclosure, terms such as“weight fraction,” “weight percentage,” and “percentage by weight” withreference to drug, or API, refers to the drug or API in the formemployed, such as in salt form, free acid form, free base form, orhydrate form. For example, a solid drug unit that has 90% by weight of adrug in salt form may include less than 90% by weight of that drug infree base form.

In one embodiment, the solid drug unit is more than 50% by weight drug.In another embodiment, 75% or more of the weight of the solid drug unitis drug, with the remainder of the weight comprising excipients, such aslubricants and binders that facilitate making the solid drug unit. Forthe purposes of this disclosure, the term “high weight fraction” withreference to the drug or API means that excipients constitute less than25 wt %, preferably less than 20 wt %, more preferably less than 15 wt%, and even more preferably less than 10 wt % of the solid drug unit. Insome cases, the drug content comprises about 75% or more of the weightof the solid drug unit. More particularly, the drug content may compriseabout 80% or more of the weight of the drug tablet. For example, thedrug content may comprise between about 85% and about 99.9% of theweight of the solid drug unit. In some embodiments, the excipientcontent can be omitted completely.

In one embodiment, the drug and excipients are selected and the soliddrug unit formulated to be water soluble, so that the solid drug unitscan be solubilized when the device is located within the bladder, torelease the solubilized drug.

The individual solid drug units may have essentially any selected shapeand dimension that fits within the devices described herein. In oneembodiment, the solid drug units are sized and shaped such that the drugreservoir lumens in the housings are substantially filled by a selectnumber of solid drug units. Each solid drug unit may have across-sectional shape that substantially corresponds to across-sectional shape of the drug reservoir lumen of a particularhousing. For example, the drug units may be substantially cylindrical inshape for positioning in a substantially cylindrical drug reservoirlumen. Once loaded, the solid drug units can, in some embodiments,substantially fill the drug reservoir lumens, forming the drug housingportion.

In one embodiment, the solid drug units are shaped to align in a rowwhen the device is in its deployment configuration. For example, eachsolid drug unit may have a cross-sectional shape that corresponds to thecross-sectional shape of the drug reservoir lumens in the housing, andeach solid drug unit may have end face shapes that correspond to the endfaces of adjacent solid drug units. The interstices or breaks betweensolid drug units can accommodate deformation or movement of the device,such as during deployment, while permitting the individual drug units toretain their solid form. Thus, the drug delivery device may berelatively flexible or deformable despite being loaded with a soliddrug, as each drug unit may be permitted to move with reference toadjacent drug units.

In embodiments in which the solid drug units are designed for insertionor implantation in a lumen or cavity in the body, such as the bladder,via a drug delivery device, the drug units may be “mini-tablets” thatare suitably sized and shaped for insertion through a natural lumen ofthe body, such as the urethra. For the purpose of this disclosure, theterm “mini-tablet” generally indicates a solid drug unit that issubstantially cylindrical in shape, having end faces and a side facethat is substantially cylindrical. The mini-tablet has a diameter,extending along the end face, in the range of about 1.0 to about 3.2 mm,such as between about 1.5 and about 3.1 mm. The mini-tablet has alength, extending along the side face, in the range of about 1.7 mm toabout 4.8 mm, such as between about 2.0 mm and about 4.5 mm. Thefriability of the tablet may be less than about 2%. Embodiments of soliddrug units and systems and methods of making the same are furtherdescribed below with reference to U.S. patents and patent Applicationsincorporated by reference herein.

In one embodiment, the drug formulation is in a solid form. In anotherembodiment, the drug formulation is in semi-solid form, such as anemulsion or suspension; a gel or a paste. For example, the drugformulation may be a highly viscous emulsion or suspension. As usedherein, the solid form includes semi-solid forms unless otherwiseindicated. In one embodiment, the drug formulation is in a liquid form.

The drug may be a low solubility drug. As used herein, the term “lowsolubility” refers to a drug having a solubility from about 0.01 mg/mLto about 10 mg/mL water at 37° C. In other embodiments, the drug is ahigh solubility drug. As used herein, the term “high solubility” refersto a drug having a solubility above about 10 mg/mL water at 37° C. Forexample, the approximate solubilities of certain drug formulations are:trospium chloride: 500 mg/mL; lidocaine HCl: 680 mg/mL; lidocaine base:8 mg/mL, gemcitabine HCl: 80 mg/mL; gemcitabine base: 15 mg/mL;oxybutynin HCl: 50 mg/mL; oxybutynin base: 0.012 mg/mL; and tolterodinetartrate: 12 mg/mL.

In one embodiment, the drug delivery device is used to treat renal orurinary tract cancer, such as bladder cancer and prostate cancer. Drugsthat may be used include antiproliferative agents, cytotoxic agents,chemotherapeutic agents, or combinations thereof. Representativeexamples of drugs which may be suitable for the treatment of urinarytract cancer include Bacillus Calmette Guerin (BCG) vaccine, docetaxel,cisplatin, doxorubicin, valrubicin, gemcitabine, mycobacterial cellwall-DNA complex (MCC), methotrexate, vinblastine, thiotepa, mitomycin(e.g., mitomycin C), fluorouracil, leuprolide, diethylstilbestrol,estramustine, megestrol acetate, cyproterone, flutamide, a selectiveestrogen receptor modulators (i.e. a SERM, such as tamoxifen), botulinumtoxins, and cyclophosphamide. The drug may comprise a monoclonalantibody, a TNF inhibitor, an anti-leukin, or the like. The drug alsomay be an immunomodulator, such as a TLR agonist, including imiquimod oranother TLR7 agonist. The drug also may be a kinase inhibitor, such as afibroblast growth factor receptor-3 (FGFR3)-selective tyrosine kinaseinhibitor, a phosphatidylinositol 3 kinase (PI3K) inhibitor, or amitogen-activated protein kinase (MAPK) inhibitor, among others orcombinations thereof. Other examples include celecoxib, erolotinib,gefitinib, paclitaxel, polyphenon E, valrubicin, neocarzinostatin,apaziquone, Belinostat, Ingenol mebutate, Urocidin (MCC), Proxinium (VB4845), BC 819 (BioCancell Therapeutics), Keyhole limpet haemocyanin, LOR2040 (Lorus Therapeutics), urocanic acid, OGX 427 (OncoGenex), and SCH721015 (Schering-Plough). The drug treatment may be coupled with aconventional radiation or surgical therapy targeted to the canceroustissue.

In one embodiment, the devices described herein are loaded with ananesthetic agent, analgesic agent, and combinations thereof. Theanesthetic agent may be an aminoamide, an aminoester, or combinationsthereof. Representative examples of aminoamides or amide-classanesthetics include articaine, bupivacaine, carticaine, cinchocaine,etidocaine, levobupivacaine, lidocaine, mepivacaine, prilocaine,ropivacaine, and trimecaine. Representative examples of aminoesters orester-class anesthetics include amylocaine, benzocaine, butacaine,chloroprocaine, cocaine, cyclomethycaine, dimethocaine, hexylcaine,larocaine, meprylcaine, metabutoxycaine, orthocaine, piperocaine,procaine, proparacaine, propoxycaine, proxymetacaine, risocaine, andtetracaine. These anesthetics typically are weak bases and may beformulated as a salt, such as a hydrochloride salt, to render themwater-soluble, although the anesthetics also can be used in free base orhydrate form. Other anesthetics, such as lontocaine, also may be used.The drug also can be an antimuscarinic compound that exhibits ananesthetic effect, such as oxybutynin or propiverine. The drug also mayinclude other drugs described herein, alone or in combination with alocal anesthetic agent.

In certain embodiments, the analgesic agent includes an opioid.Representative examples of opioid agonists include alfentanil,allylprodine, alphaprodine, anileridine, benzylmorphine, bezitramide,buprenorphine, butorphanol, clonitazene, codeine, desomorphine,dextromoramide, dezocine, diampromide, diamorphone, dihydrocodeine,dihydromorphine, dimenoxadol, dimepheptanol, dimethylthiambutene,dioxaphetyl butyrate, dipipanone, eptazocine, ethoheptazine,ethylmethylthiambutene, ethylmorphine, etonitazene fentanyl, heroin,hydrocodone, hydromorphone, hydroxypethidine, isomethadone,ketobemidone, levorphanol, levophenacylmorphan, lofentanil, meperidine,meptazinol, metazocine, methadone, metopon, morphine, myrophine,nalbuphine, narceine, nicomorphine, norlevorphanol, normethadone,nalorphine, normorphine, norpipanone, opium, oxycodone, oxymorphone,papaveretum, pentazocine, phenadoxone, phenomorphan, phenazocine,phenoperidine, piminodine, piritramide, proheptazine, promedol,properidine, propiram, propoxyphene, sufentanil, tilidine, tramadol,pharmaceutically acceptable salts thereof, and mixtures thereof. Otheropioid drugs, such as mu, kappa, delta, and nociception opioid receptoragonists, are contemplated.

Representative examples of other suitable pain relieving agents includesuch agents as salicyl alcohol, phenazopyridine hydrochloride,acetaminophen, acetylsalicylic acid, flufenisal, ibuprofen, indoprofen,indomethacin, and naproxen.

In certain embodiments, the drug delivery device is used to treatinflammatory conditions such as interstitial cystitis (IC), radiationcystitis, painful bladder syndrome, prostatitis, urethritis,post-surgical pain, and kidney stones. Non-limiting examples of specificdrugs for these conditions include lidocaine, glycosaminoglycans (e.g.,chondroitin sulfate, sulodexide), pentosan polysulfate sodium (PPS),dimethyl sulfoxide (DMSO), oxybutynin, mitomycin C, heparin, flavoxate,ketorolac, cyclosporine, or combinations thereof. For kidney stones, thedrug(s) may be selected to treat pain and/or to promote dissolution ofrenal stones.

Other non-limiting examples of drugs that may be used in the treatmentof IC include nerve growth factor monoclonal antibody (MAB) antagonists,such as Tanezumab, and calcium channel alpha-2-delta modulators, such asPD-299685 or gabepentin. Evidence suggests that the bladder expressesnerve growth factor (NGF) locally, since exogenously delivered NGF intothe bladder induces bladder hyperactivity and increases the excitabilityof dissociated bladder afferent neurons (Nature Rev Neurosci 2008;9:453-66). Accordingly, it would be advantageous to locally deliver aMAB or other agent against NGF using the described delivery devices,significantly reducing the total dose needed for therapeutic efficacy.Evidence also suggests that binding of the alpha-2-delta unit ofvoltage-sensitive calcium channels, such as with gabapentin, may beeffective in the treatment of diseases of neuropathic pain such asfibromyalgia and that there may be common mechanisms between IC anddiseases of neuropathic pain (See Tech Urol. 2001 March, 7(1):47-49).Accordingly, it would be advantageous to locally deliver a calciumchannel alpha-2-delta modulator, such as PD-299685 or gabepentin, usingthe described delivery devices, minimizing does-related systemictoxicities in the treatment of IC.

Other intravesical cancer treatments include small molecules, such asApaziquone, adriamycin, AD-32, doxorubicin, doxetaxel, epirubicin,gemcitabine, HTI-286 (hemiasterlin analogue), idarubicin, γ-linolenicacid, mitozantrone, meglumine, and thiotepa; large molecules, such asEGF-dextran, HPC-doxorubicin, IL-12, IFN-α2b, IFN-γ, α-lactalbumin, p53adenovector, TNFα; combinations, such as Epirubicin+BCG,IFN+farmarubicin, Doxorubicin+5-FU (oral), BCG+IFN, and Pertussistoxin+cystectomy; activated cells, such as macrophages and T cells;intravesical infusions such as IL-2 and Doxorubicin; chemosensitizers,such as BCG+antifirinolytics (paramethylbenzoic acid or aminocaproicacid) and Doxorubicin+verapimil; diagnostic/imaging agents, such asHexylaminolevulinate, 5-aminolevulinic acid, Iododexyuridine, HMFG1Mab+Tc99m; and agents for the management of local toxicity, such asFormaline (hemorrhagic cystitis).

The drug delivery device can be used, for example, to treat urinaryincontinence, frequency, or urgency, including urge incontinence andneurogenic incontinence, as well as trigonitis. Drugs that may be usedinclude anticholinergic agents, antispasmodic agents, antimuscarinicagents, β-2 agonists, alpha adrenergics, anticonvulsants, norepinephrineuptake inhibitors, serotonin uptake inhibitors, calcium channelblockers, potassium channel openers, and muscle relaxants.Representative examples of suitable drugs for the treatment ofincontinence include oxybutynin, S-oxybutytin, emepronium, verapamil,imipramine, flavoxate, atropine, propantheline, tolterodine, rociverine,clenbuterol, darifenacin, terodiline, trospium, hyoscyamin, propiverine,desmopressin, vamicamide, clidinium bromide, dicyclomine HCl,glycopyrrolate aminoalcohol ester, ipratropium bromide, mepenzolatebromide, methscopolamine bromide, scopolamine hydrobromide, iotropiumbromide, fesoterodine fumarate, YM-46303 (Yamanouchi Co., Japan),lanperisone (Nippon Kayaku Co., Japan), inaperisone, NS-21 (NipponShinyaku Orion, Formenti, Japan/Italy), NC-1800 (Nippon Chemiphar Co.,Japan), ZD-6169 (Zeneca Co., United Kingdom), and stilonium iodide.

In still another embodiment, the present intravesical drug deliverydevices are used to treat infections involving the bladder, theprostate, the kidney, and the urethra. Antibiotics, antibacterial,antifungal, antiprotozoal, antiseptic, antiviral and other antiinfectiveagents can be administered for treatment of such infections.Representative examples of drugs for the treatment of infections includemitomycin, ciprofloxacin, norfloxacin, ofloxacin, methanamine,nitrofurantoin, ampicillin, amoxicillin, nafcillin, trimethoprim,sulfonamides trimethoprimsulfamethoxazole, erythromycin, doxycycline,metronidazole, tetracycline, kanamycin, penicillins, cephalosporins, andaminoglycosides.

In other embodiments, the drug delivery device is used to treat fibrosisof a genitourinary site, such as the bladder or uterus. Representativeexamples of drugs for the treatment of fibroids include pentoxphylline(xanthine analogue), antiTNF, antiTGF agents, GnRH analogues, exogenousprogestins, antiprogestins, selective estrogen receptor modulators,danazol and NSAIDs.

The implantable drug delivery devices also may be used to treat spasticor flaccid neurogenic bladder. Representative examples of drugs for thetreatment of neurogenic bladder include analgesics or anaesthetics, suchas lidocaine, bupivacaine, mepivacaine, prilocaine, articaine, andropivacaine; anticholinergics; antimuscarinics such as oxybutynin orpropiverine; a vanilloid, such as capsaicin or resiniferatoxin;antimuscarinics such as ones that act on the M3 muscarinic acetylcholinereceptor (mAChRs); antispasmodics including GABA_(B) agonists such asbaclofen; botulinum toxins; capsaicins; alpha-adrenergic antagonists;anticonvulsants; serotonin reuptake inhibitors such as amitriptyline;and nerve growth factor antagonists. In various embodiments, the drugmay be one that acts on bladder afferents or one that acts on theefferent cholinergic transmission, as described in Reitz et al., SpinalCord 42:267-72 (2004).

In one embodiment, the drug is selected from those known for thetreatment of incontinence due to neurologic detrusor overactivity and/orlow compliant detrusor. Examples of these types of drugs include bladderrelaxant drugs (e.g., oxybutynin (antimuscarinic agent with a pronouncedmuscle relaxant activity and local anesthetic activity), propiverine,impratroprium, tiotropium, trospium, terodiline, tolterodine,propantheline, oxyphencyclimine, flavoxate, and tricyclicantidepressants); drugs for blocking nerves innervating the bladder andurethra (e.g., vanilloids (capsaicin, resiniferatoxin), botulinum-Atoxin); or drugs that modulate detrusor contraction strength,micturition reflex, detrusor sphincter dyssynergia (e.g., GABAb agonists(baclofen), benzodiazapines). In another embodiment, the drug isselected from those known for the treatment of incontinence due toneurologic sphincter deficiency. Examples of these drugs include alphaadrenergic agonists, estrogens, beta-adrenergic agonists, tricyclicantidepressants (imipramine, amitriptyline). In still anotherembodiment, the drug is selected from those known for facilitatingbladder emptying (e.g., alpha adrenergic antagonists (phentolamine) orcholinergics). In yet another embodiment, the drug is selected fromamong anticholinergic drugs (e.g., dicyclomine), calcium channelblockers (e.g., verapamil) tropane alkaloids (e.g., atropine,scopolamine), nociceptin/orphanin FQ, and bethanechol (e.g., m3muscarinc agonist, choline ester).

In certain embodiments, the drug is a steroid, such as triamcinolone,budesonide, or prednisolone. In certain embodiments, the drug islidocaine, gemcitabine, docetaxel, carboplatin, cisplatin, oxaliplatin,trospium, tolterodine, oxybutynin, or mitomycin C.

Other Device Features

The devices described herein may include a radio-opaque portion orstructure to facilitate detection or viewing (e.g., by X-ray imaging orfluoroscopy) of the device by a medical practitioner as part of theimplantation or retrieval procedure. In one embodiment, the housing isconstructed of a material that includes a radio-opaque filler material,such as barium sulfate or another radio-opaque material known in theart. Some housings may be made radio-opaque by blending radio-opaquefillers, such as barium sulfate or another suitable material, during theprocessing of the material from which the housing is formed. Theradio-opaque material may be associated with the retention frame inthose embodiments that include a retention frame. Ultrasound imaging orfluoroscopy may be used to image the device in vivo.

The drug delivery device may further include a retrieval feature, suchas a string, a loop, or other structure that facilitates removal of thedevice from the body cavity, for example for removal of a non-resorbabledevice body following release of the drug formulation from the soliddrug units. In one case, the device may be removed from the bladder byengaging the string to pull the device through the urethra. The devicemay be configured to assume a relatively narrow or linear shape whenpulling the device by the retrieval feature into the lumen of a catheteror cystoscope or into the urethra.

Methods for Drug Delivery

The devices and methods disclosed herein may be adapted for use inhumans, whether male or female, adult or child, or for use in animals,such as for veterinary or livestock applications. Accordingly, the term“patient” may refer to a human or other mammalian subject.

In certain embodiments, a method of administering a drug to a patientincludes inserting a drug delivery device into a patient and permittingthe drug to be released from the device. For example, the device mayinclude any features, or combinations of features, described herein. Inone embodiment, the drug is released from the drug reservoir lumen viadiffusion through the second material of the second annular segment ofthe wall structure. In embodiments in which the wall structure comprisesfirst and second wall structures, the method includes releasing the drugfrom the drug reservoir lumen via diffusion through the second wallstructure.

In certain embodiments, permitting the drug to be released from thedevice includes permitting water to be imbibed through the waterpermeable wall portions or segments (e.g., through only the second wallstructure/second material or through both the first and second wallstructures/materials to solubilize the drug), and permitting thesolubilized drug to be released from the device by diffusion through thesecond wall structure/material. That is, in certain embodiments, elutionof drug from the device occurs following dissolution of the drug withinthe device. Bodily fluid enters the device, contacts the drug andsolubilizes the drug, and thereafter the dissolved drug diffuses fromthe device. For example, the drug may be solubilized upon contact withurine in cases in which the device is implanted in the bladder. In oneembodiment, releasing the drug from the device includes solubilizing thedrug with water imbibed through the second wall structure/material, orboth the first and second wall structures/materials.

In certain embodiments, the inserting comprises deploying the devicethrough the patient's urethra and into the patient's urinary bladder.The device may be implanted non-surgically and may deliver drug forseveral days, weeks, months, or more after the implantation procedurehas ended. In one embodiment, deploying the drug delivery device in thepatient includes inserting the device into a body cavity or lumen of thepatient via a deployment instrument. For example, the device may bedeployed through a deployment instrument, such as a catheter orcystoscope, positioned in a natural lumen of the body, such as theurethra, or into a body cavity, such as the bladder. The deploymentinstrument typically is removed from the body lumen while the drugdelivery device remains in the bladder or other body cavity for aprescribed treatment period.

The device, in some embodiments, may be deployed into the bladder of apatient in an independent procedure or in conjunction with anotherurological or other procedure or surgery, either before, during, orafter the other procedure. The device may release one or more drugs thatare delivered to local and/or regional tissues for therapy orprophylaxis, either peri-operatively, post-operatively, or both.

In one example, the device is deployed by passing the drug deliverydevice through a deployment instrument and releasing the device from thedeployment instrument into the body. In cases in which the device isdeployed into a body cavity such as the bladder, the device assumes aretention shape, such as an expanded or higher profile shape, once thedevice emerges from the deployment instrument into the cavity. Thedeployment instrument may be any suitable lumen device, such as acatheter, e.g., a urethral catheter, or cystoscope. These terms are usedinterchangeably herein, unless otherwise expressly indicated. Thedeployment instrument may be a commercially available device or a devicespecially adapted for the present drug delivery devices. In oneembodiment, deploying the drug delivery device in the patient includes(i) elastically deforming the device into the relatively straightenedshape; (ii) inserting the device through the patient's urethra; and(iii) releasing the device into the patient's bladder such that itassumes the coiled retention shape.

The drug delivery device may be passed through the deploymentinstrument, driven by a stylet or flow of lubricant or other fluid, forexample, until the drug delivery device exits a lumen of the instrumentas passes into the bladder. Thus, the device may be implanted into thebladder of a male or female human patient in need of treatment, eitheradult or child.

Once deployed in vivo, the device subsequently may release one or moredrugs for the treatment of one or more conditions, locally to one ormore tissues at the deployment site and/or regionally to other tissuesdistal from the deployment site. The release may be controlled and mayrelease the drug in an effective amount over an extended period.Thereafter, the device may be removed, resorbed, excreted, or somecombination thereof. In certain embodiments, the device resides in thebladder releasing the drug over a predetermined period, such as twoweeks, three weeks, four weeks, a month, or more.

Once implanted, the device may provide extended, continuous,intermittent, or periodic release of a desired quantity of drug over adesired, predetermined period. In embodiments, the device can deliverthe desired dose of drug over an extended period, such as 12 hours, 24hours, 5 days, 7 days, 10 days, 14 days, or 20, 25, 30, 45, 60, or 90days, or more. The rate of delivery and dosage of the drug can beselected depending upon the drug being delivered and the disease orcondition being treated. In one embodiment, a rate of release of thedrug from the drug delivery device is zero order over at least 36 hours.In one embodiment, a rate of the release of the drug from the drugdelivery device is essentially zero order over at least 7 days.

The device may be used to treat interstitial cystitis, radiationcystitis, pelvic pain, bladder inflammation, overactive bladdersyndrome, bladder cancer, neurogenic bladder, neuropathic ornon-neuropathic bladder-sphincter dysfunction, infection, post-surgicalpain or other diseases, disorders, and conditions treated with drugsdelivered to the bladder. The device may release drug locally to thebladder and regionally to other sites near the bladder. The device maydeliver drugs that improve bladder function, such as bladder capacity,compliance, and/or frequency of uninhibited contractions, that reducepain and discomfort in the bladder or other nearby areas, or that haveother effects, or combinations thereof. The bladder-deployed device alsomay deliver a therapeutically effective amount of one or more drugs toother genitourinary sites within the body, such as other locationswithin urological or reproductive systems of the body, including thekidneys, urethra, ureters, penis, testes, seminal vesicles, vasdeferens, ejaculatory ducts, prostate, vagina, uterus, ovaries, orfallopian tubes, among others or combinations thereof. For example, thedrug delivery device may be used in the treatment of kidney stones orfibrosis, erectile dysfunction, among other diseases, disorders, andconditions.

In one embodiment, the device may have two payloads of drug that arereleased at different times. The first payload may be adapted forrelatively quick release, while the second payload may be adapted formore continuous release.

Subsequently, the device may be retrieved from the body, such as incases in which the device is non-resorbable or otherwise needs to beremoved. Retrieval devices for this purpose are known in the art or canbe specially produced. The device also may be completely or partiallybioerodible, resorbable, or biodegradable, such that retrieval isunnecessary, as either the entire device is resorbed or the devicesufficiently degrades for expulsion, for example, from the bladderduring urination. The device may not be retrieved or resorbed until someof the drug, or preferably most or all of the drug, has been released.If needed, a new drug-loaded device may subsequently be implanted,during the same procedure as the retrieval or at a later time.

Methods of Making the Device

The devices described herein generally are formed by using aco-extrusion process to form the elongated, elastic housing of thedevice; loading the drug reservoir lumen with a suitable quantity of thedrug (optionally formulated with one or more excipients); and closingoff the ends of the tubular housing.

In embodiments in which the drug permeable portion does not extend alongthe entire length of the elongated housing, the method of making thedevice includes forming the first annular segment by an extrusionprocess which comprises introducing the first material into an extrusionstream; and forming the second annular segment by intermittentlyintroducing the second material into the extrusion stream with the firstmaterial at preselected positions, in a manner effective to form atubular structure comprising one or more first annular segmentsintegrally connected to one or more second annular segments. Inparticular, the first and second materials are located in the extrusionstream such that, in the second annular segment, the first materialforms a first arcuate portion and the second material forms a secondarcuate portion, wherein the first and second arcuate portions areintegrally connected and together defining the annulus of the secondannular segment. The method further includes cutting the tubularstructure at one or more positions to form the elongated, elastichousing; loading a drug into the drug reservoir lumen; and sealing thefirst and second ends of the drug reservoir lumen. With this method, theresulting device may have a tubular wall structure as illustrated inFIGS. 8A-8D, FIGS. 9A-9B.

In another embodiment, the method of making the device includes formingthe first annular segment by an extrusion process which comprisesintroducing the first material into an extrusion stream; and forming thesecond annular segment by intermittently introducing the second materialinto the extrusion stream to replace the first material along a selectedlength of the extrusion stream, in a manner effective to form a tubularstructure comprising two or more first annular segments integrallyconnected to two or more second annular segments. In particular, thefirst annular segment is formed entirely of a first material which isimpermeable to the drug, and the second annular segment is formedprimarily of a second material which is permeable to the drug andconfigured to release the drug in vivo by diffusion through the secondmaterial. The term “primarily” is used to denote that any transitionregions are, for purposed of description, included second annularsegment. The method further includes cutting the tubular structure atone or more positions to form the elongated, elastic housing; loading adrug into the drug reservoir lumen; and sealing the first and secondends of the housing. With this method, the resulting device may have atubular wall structure as illustrated in FIGS. 10A-10D.

In some embodiments, the tubular wall structure may include a retentionlumen extending through the structure. The retention lumen optionallymay be loaded with an elastic retention frame, such as a nitinol wire orother superelastic wire, and then sealed to keep the frame inside thelumen and/or optionally may be filled with a gas (e.g., air) and thensealed at its ends prior or subsequent to drug loading of the device. Inanother embodiment, the retention lumen may be filled with highdurometer silicone, prior to drug loading of the device, which is thencured into a solid, elastic form effective to bias the tubular wallstructure in the coiled bladder retention shape.

In other embodiments, the method includes thermally shape setting thetubular structure to have a coiled retention shape which is elasticallydeformable into an uncoiled shape. In such embodiments, a retentionlumen and frame advantageously may not be necessary.

Some steps or sub-steps of the method of making a drug delivery devicemay be performed in other orders or simultaneously.

The present disclosure may be further understood with reference to thefollowing non-limiting examples.

EXAMPLES

A study was performed to determine whether thermoplastic materials couldbe used to form a tubular drug housing that is thermally shaped to havea retention shape suited to retain the drug housing in the bladder andthat is elastically deformable to a relatively straightened shape suitedfor insertion through a lumen into the bladder, without a retentionframe or wire. A blended polymer material containing aliphaticpolyether-based thermoplastic polyurethane Tecoflex™ (EG-80A) (LubrizolCorp.) in an amount of 50 percent, by weight, and aliphatic, hydrophilicpolyether-based thermoplastic polyurethane Tecophilic™ (HP-93A-100)(Lubrizol Corp.) in an amount of 50 percent, by weight, was formed intoa tube having an inner diameter of about 2.16 mm and a wall thickness ofabout 0.81 mm.

A tube having a length of about 15 cm was bent and shaped thermallyusing a hot plate, heat gun, and wire fixture, to have a coiled, orpretzel-like, shape essentially consisting of two sub-circles, eachhaving its own smaller arch and sharing a common larger arch. Then,Lactose tablets (diameter of about 2.16 mm) were inserted into in alength of about 13 cm and the ends of the tube were sealed by 2.77 mm(outer diameter) silicone spacers that were mechanically inserted intothe ends.

Degassed deionized water (300 g) was poured into a beaker and the tubesystem was placed in the beaker, which then was placed in a 37° C.chamber with the top covered with parafilm.

Thus, it was concluded that a thermoplastic material (e.g., polyurethaneblend) could be used to form a tubular drug housing that is thermallyshaped to have a retention shape, in the absence of a retention frame orwire.

Another length of tubing was formed according to the above-describedmethod, but was bent and shaped thermally using a hot plate, heat gun,and wire fixture, to have a multi-coil shape essentially consisting offour sub-circles, each having its own smaller arch and sharing a commonlarger arch with the adjacent sub-circle(s).

Many modifications and other implementations of the disclosure set forthherein will be apparent having the benefit of the teachings presented inthe foregoing descriptions and the associated drawings. Therefore, it isto be understood that the disclosure is not to be limited to thespecific implementations disclosed and that modifications and otherimplementations are intended to be included within the scope of theappended claims. Although specific terms are employed herein, they areused in a generic and descriptive sense only and not for purposes oflimitation.

I claim:
 1. A drug delivery device comprising: an elongated, elastichousing having a drug reservoir lumen extending between a first closedend and a second closed end; and a drug contained in the drug reservoirlumen, wherein: the housing comprises a tubular wall structure whichcomprises: a first annular segment formed entirely of a first materialwhich is impermeable to the drug, and a second annular segment formed atleast partially of a second material which is permeable to the drug andconfigured to release the drug in vivo by diffusion through the secondmaterial in the second annular segment, and the first annular segmenthas a first end which is integrally formed and connected with a firstend of the second annular segment.
 2. The device of claim 1, wherein thesecond annular segment is formed of the first material and the secondmaterial.
 3. The device of claim 2, wherein in the second annularsegment, the first material forms a first arcuate portion and the secondmaterial forms a second arcuate portion, the first and second arcuateportions being integrally connected and together defining the annulus ofthe second annular segment.
 4. The device of claim 3, wherein the secondarcuate portion has an arc angle from 15 degrees to 120 degrees.
 5. Thedevice of claim 3, wherein the second arcuate portion has an arc anglefrom 30 degrees and 60 degrees.
 6. The device of claim 1, wherein thesecond annular segment is formed primarily of the second material. 7.The device of claim 1, wherein the first and second annular segments areformed together in an extrusion process.
 8. The device of claim 1,wherein the tubular wall structure further comprises a third annularsegment which is formed entirely of the first material and which isintegrally formed and connected with an opposed second end of the secondannular segment.
 9. The device of claim 8, wherein the second and thirdannular segments are formed together in the extrusion process.
 10. Thedevice of claim 1, wherein the tubular wall structure has a total length(L_(T)) between opposed ends of the housing and the second annularsegment has a length (L) which is from 5% to 50% of the total length(L_(T)).
 11. The device of claim 1, wherein the first material comprisessilicone, thermoplastic polyurethane, or ethylene-vinyl acetate (EVA).12. The device of claim 1, wherein the second material comprises ahydrophilic thermoplastic polyurethane.
 13. The device of claim 1,wherein the device is configured to be elastically deformable from acoiled retention shape suited to retain the device within the urinarybladder of a patient to an uncoiled shape suited for insertion throughthe patient's urethra and into the bladder, in the absence of a wireretention frame.
 14. The device of claim 1, wherein the drug is in theform of a plurality of solid tablets.
 15. A drug delivery devicecomprising: a tubular housing having a closed drug reservoir lumenbounded by a wall structure comprising at least one thermoplasticmaterial; and a drug contained in the drug reservoir lumen, wherein: atleast a portion of the wall structure is water permeable, at least aportion of the wall structure is permeable to the drug such that thedrug is releasable in vivo by diffusion through the drug permeableportion of the wall structure, the tubular housing is thermally shapeset to have a coiled retention shape suited to retain the device withinthe urinary bladder of a patient and is elastically deformable from thecoiled retention shape to an uncoiled shape suited for insertion of thedevice through the patient's urethra and into the bladder, and the wallstructure comprises: (i) a first annular segment formed entirely of afirst material which is impermeable to the drug, and (ii) a secondannular segment formed at least partially of a second material which ispermeable to the drug and configured to release the drug in vivo bydiffusion through the second material in the second annular segment,wherein the first annular segment has a first end which is integrallyformed and connected with a first end of the second annular segment. 16.The device of claim 15, wherein the first material comprises a firstthermoplastic polyurethane composition and the second material comprisesa second thermoplastic polyurethane composition which is different fromthe first thermoplastic polyurethane composition.
 17. The device ofclaim 15, wherein the first and second wall structures are integrallyformed in a coextrusion process.
 18. The device of claim 15, wherein thecoiled retention shape comprises at least one loop having a radius ofcurvature of at least 0.5 cm.
 19. The device of claim 15, wherein thedrug is in the form of a plurality of solid tablets.
 20. A method ofadministering a drug to a patient in need thereof, comprising: insertinginto the patient the device of claim 1; permitting water to be imbibedthrough the tubular wall structure to solubilize the drug; andpermitting the solubilized drug to be released from the device bydiffusion through the second annular segment of the tubular wallstructure.